Project Summary/Abstract Learning to respond automatically to stimuli in the environment allows individuals to operate efficiently under stable conditions. However, under changing conditions, the ability to flexibly override automatic responses is essential for optimizing behavior. Our preliminary data from the previous funding cycle suggest that adolescent alcohol exposure impairs behavioral flexibility, with effects persisting into adulthood. Specifically, we find that binge drinking during human adolescence is associated with heightened sensitivity of the attention system to reward-associated cues. Similarly, adolescent intermittent ethanol (AIE) exposure in rats results in enhanced approach to reward-associated cues. Currently, we don?t know whether these forms of behavioral inflexibility are related to the tendency to express habitual actions that are relatively inflexible and associated with chronic alcohol exposure. Furthermore, we don?t know whether either behavioral tendency correlates with the hypo- frontal connectivity also associated with AIE, nor whether manipulation of frontal circuits can modulate these forms of behavioral flexibility. Answering these questions is critically important, as habitual responses to reward-associated cues may facilitate compulsive alcohol use and contribute to relapse among people with alcohol use disorders (AUDs). Replacing habitual responses to alcohol cues with new actions yielding better outcomes is a key element of recovery from AUDs. While we know much about the neural regulation of habitual versus goal-directed responding, particularly in animal models, and we have some idea about the effects of adult alcohol exposure, we understand much less about the impact of adolescent alcohol exposure on such behavioral flexibility. We propose a unique translational approach to probe the neurobiological bases of the ability to form and to flexibly overcome automatic actions and to evaluate theoretically based interventions to bidirectionally modulate behavioral flexibility. Our core hypothesis, supported by our preliminary data, is that adolescent binge alcohol exposure promotes both an overreliance on stimulus- response (S-R) action selection strategy (habit) and hypersensitivity to reward conditioning in adulthood via common alterations in shared underlying neural circuits. Moreover, the relationship between reliance on habit and sensitivity to reward conditioning is mediated by neural circuit changes impairing top-down control of responses to salient exogenous cues. We now propose to use resting-state fMRI to identify differences in brain circuit function associated with impairment in overriding automatic S-R associations and sensitivity to reward conditioning. We will also test whether bidirectional manipulation of frontal cortex can promote or reduce top- down control over behavior, thereby ameliorating or mimicking the impairment associated with adolescent alcohol exposure. This work will identify objective targets for use in developing novel treatments to promote flexible, goal-directed actions over deleterious automatic actions. This approach may substantially improve our ability to cope with the public health challenges of AUDs, a leading cause worldwide of preventable death.